HPV testing and the long term risk at cervical disease

In the Netherlands each year approximately 8000 women are treated for a
high-grade pre-malignant cervical lesion. The majority of these lesions are
detected in the population based cervical cancer screening program, in which
exfoliated cells of the cervix are microscopically examined.
A disadvantage of the current (cytological) test is the poor sensitivity
(around 60%), leading to false-negative results. Since a persistent infection
with human papillomavirus (HPV) is the key causative agent in the development
of cervical lesions, women at risk can be identified by a HPV test (GP5+/6+
primer-mediated PCR with enzyme immuno assay read-out). This test has a
sensitivity of approximately 90% and a negative predictive value of almost 100%
for high-grade pre-malignant lesions measured over a short period of time (up
to 2 years). In order to give a well-founded advice how to adjust the screening
test for cervical cancer to the HPV test, the predictive value on the long term
development of cervical abnormalities has to be known.

The primary objectives of our study are:
- Determining the long-term predictive value of a positive HPV test for
(pre)malignant cervical disease.
- Determining the long-term protective value of a negative HPV test.
- Determining the long-term protective value of a negative cervical smear test.

The secondary objectives of our study are:
- Determining the cumulative incidence of cervical disease in the investigated
group.
- Comparison of the long term predictive value of the HPV test to cytology.
- Determining acquisition of HPV infection in women with a previous cytological
abnormality.
- Evaluation of the presence of E6/E7 antibodies in women with an abnormal
smear history.
- Comparison of the cost-effectiveness of the HPV test to the current situation
of cytology.

The study is designed as an open prospective longitudinal clinical cohort study.
A flow chart of the study is presented at page 17 of the protocol.

In this study we will follow up the cohort described in the study conducted by
Nobbenhuis et al. *Relation of Human papillomavirus status to cervical lesions
and consequences for cervical cancer screening: A prospective study*.
We will contact all subjects by phone to check the current addresses and to
give a brief overview of the study.

During the visit at the outpatients clinic, which takes approximately 30
minutes all together, the following acts are scheduled:
- Check if patient information form has been read and understood.
- Check inclusion and exclusion criteria.
- Obtain written informed consent. All enrolled subjects must sign an original
informed consent form in duplicate prior to
any study procedures.
- Assign a study number for all study procedures.
- Collect gynecological history.
- Complete questionnaire.
- Collect a cervical (vaginal) sample for HPV testing as well as for
cytological evaluation.
- Collect a blood sample
- Verify if the subject agrees to inform the general practitioner about the
results of the tests.
- Make an appointment to discuss the results, in case the result of the
cervical smear is *abnormal* (classified CISOE-A * S2, E3 or O3) or if the
subject is tested hrHPV positive a follow-up visit will be scheduled in order
to perform a colposcopy by an experienced colposcopist.

In case the subject participates by self-sampling, a colposcopic axamination
will be planned in case a high-risk HPV type is present.

The possible benefit for the participating subject may be the earlier detection
of a cervical lesion in comparison to those subjects who only participate in
the population based screening program.

Risks and burden are linked to protocol procedures, such as blood withdrawal,
cervical sampling and, if applicable colposcopy. Although these are routine
procedures, carried out by medical qualified personnel, they may cause side
effects or discomfort to the subject. However, it is expected that these
procedures will generally be well tolerated.